Mechanism of Action

Methylnaltrexone bromide is a selective antagonist of opioid binding at the mu-opioid receptor. As a quaternary amine, the ability of methylnaltrexone bromide to cross the blood-brain barrier is restricted. This allows methylnaltrexone bromide to function as a peripherally-acting mu-opioid receptor antagonist in tissues such as the gastrointestinal tract, thereby decreasing the constipating effects of opioids without impacting opioid-mediated analgesic effects on the central nervous system.

Pharmacodynamics

Use of opioids induces slowing of gastrointestinal motility and transit. Antagonism of gastrointestinal mu-opioid receptors by methylnaltrexone bromide inhibits opioid-induced delay of gastrointestinal transit time in a dose-dependent manner in rats. The effects of methylnaltrexone bromide on central mu-opioid receptors were evaluated in a pharmacodynamic study in which subjects received a dose of remifentanil, sufficient to produce pupiliary constriction, followed by placebo, naloxone, or methylnaltrexone. Following remifentanil administration, the methylnaltrexone and placebo groups showed no change in pupiliary constriction while the naloxone group showed a marked change over the time interval tested.

Pharmacokinetics

Absorption

Following subcutaneous administration, methylnaltrexone bromide is absorbed rapidly, with peak concentrations (Cmax) achieved at approximately 0.5 hours. Across the range of doses evaluated peak plasma concentration and area under the plasma concentration-time curve (AUC) increase in a dose-proportional manner, as shown in the table below.

PHARMACOKINETIC PARAMETERS OF METHYLNALTREXONE BROMIDE FOLLOWING SINGLE SUBCUTANEOUS DOSES

Distribution

Methylnaltrexone bromide undergoes moderate tissue distribution. The steady-state volume of distribution (Vss) is approximately 1.1 L/kg. The fraction of methylnaltrexone bromide bound to human plasma proteins is 11.0% to 15.3%, as determined by equilibrium dialysis.

Metabolism

In a mass balance study, approximately 60% of the administered radioactivity recovered with 5 distinct metabolites and none of the detected metabolites was in amounts over 6% of administered radioactivity. Conversion to methyl-6-naltrexol isomers (5% of total) and methylnaltrexone sulfate (1.3% of total) appear to be the primary pathways of metabolism. N-demethylation of methylnaltrexone to produce naltrexone is not significant.

Excretion

Methylnaltrexone bromide is eliminated primarily as the unchanged drug (85% of administered radioactivity). Approximately half of the dose is excreted in the urine and somewhat less in feces. The terminal half-life (t_1/2) is approximately 8 hours.

Effect on Cardiac Repolarization

In a randomized, double blind placebo- and (open-label) moxifloxacin-controlled 4-period crossover study, 56 healthy subjects were administered methylnaltrexone bromide 0.3 mg/kg and methylnaltrexone bromide 0.64 mg/kg by IV infusion over 20 minutes, placebo, and a single oral dose of moxifloxacin. At both the 0.3 mg/kg and 0.64 mg/kg methylnaltrexone bromide doses, no significant effect on the QTc interval was detected.

Animal Toxicology and/or Pharmacology

A single subcutaneous dose of 500 mg/kg of methylnaltrexone bromide was not lethal to rats.

Reproduction studies have been performed in pregnant rats at intravenous doses up to 25 mg/kg/day (about 14 times the recommended maximum human subcutaneous dose of 0.3 mg/kg based on the body surface area) and in pregnant rabbits at intravenous doses up to 16 mg/kg/day (about 17 times the recommended maximum human subcutaneous dose based on the body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to methylnaltrexone bromide.

In an in vitro human cardiac potassium ion channel (hERG) assay, methylnaltrexone bromide caused concentration-dependent inhibition of hERG current (1%, 12%, 13% and 40% inhibition at 30, 100, 300 and 1000 µM concentrations, respectively). Methylnaltrexone bromide had a hERG IC₅₀ of > 1000 µM. In isolated dog Purkinje fibers, methylnaltrexone bromide caused prolongations in action potential duration (APD). The highest tested concentration (10 µM) in the dog Purkinje fiber study was about 18 and 37 times the Cmax at human subcutaneous (SC) doses of 0.3 and 0.15 mg/kg, respectively. In isolated rabbit Purkinje fibers, methylnaltrexone bromide (up to 100 µM) did not have an effect on APD, compared to vehicle control. The highest methylnaltrexone bromide concentration (100 µM) tested was about 186 and 373 times the human Cmax at SC doses of 0.3 and 0.15 mg/kg, respectively. In anesthetized dogs, methylnaltrexone bromide caused decreases in blood pressure, heart rate, cardiac output, left ventricular pressure, left ventricular end diastolic pressure, and +dP/dt at ≥ 1 mg/kg. In conscious dogs, methylnaltrexone bromide caused a dose-related increase in QTc interval. After a single IV dosage of 20 mg/kg to beagle dogs, predicted Cmax and AUC values were approximately 482 and 144 times, respectively, the exposure at human SC dose of 0.15 mg/kg and 241 times and 66 times, respectively, the exposure at a human SC dose of 0.3 mg/kg. In conscious guinea pigs, methylnaltrexone caused mild prolongation of QTc (4% over baseline) at 20 mg/kg, IV. A thorough QTc assessment was conducted in humans [see Pharmacoldnetics].

Clinical Studies

The efficacy and safety of RELISTOR (methylnaltrexone bromide) in the treatment of opioid-induced constipation in advanced illness patients receiving palliative care was demonstrated in two randomized, double-blind, placebo-controlled studies. In these studies, the median age was 68 years (range 21-100); 51% were females. In both studies, patients had advanced illness with a life expectancy of less than 6 months and received care to control their symptoms. The majority of patients had a primary diagnosis of incurable cancer; other primary diagnoses included end-stage COPD/emphysema, cardiovascular disease/heart failure, Alzheimer's disease/dementia, HIV/AIDS, or other advanced illnesses. Prior to screening, patients had been receiving palliative opioid therapy (median daily baseline oral morphine equivalent dose =172 mg), and had opioid-induced constipation (either < 3 bowel movements in the preceding week or no bowel movement for > 2 days). Patients were on a stable opioid regimen ≥ 3 days prior to randomization (not including PRN or rescue pain medication) and received their opioid medication during the study as clinically needed. Patients maintained their regular laxative regimen for at least 3 days prior to study entry, and throughout the study. Rescue laxatives were prohibited from 4 hours before to 4 hours after taking an injection of study medication.

Study 1 compared a single, double-blind, subcutaneous dose of RELISTOR (methylnaltrexone bromide) 0.15 mg/kg, or RELISTOR (methylnaltrexone bromide) 0.3 mg/kg versus placebo. The double-blind dose was followed by an open-label 4-week dosing period, where RELISTOR (methylnaltrexone bromide) could be used as needed, no more frequently than 1 dose in a 24 hour period. Throughout both study periods, patients maintained their regular laxative regimen. A total of 154 patients (47 RELISTOR (methylnaltrexone bromide) 0.15 mg/kg, 55 RELISTOR (methylnaltrexone bromide) 0.3 mg/kg, 52 placebo) were enrolled and treated in the double-blind period. The primary endpoint was the proportion of patients with a rescue-free laxation within 4 hours of the double-blind dose of study medication. RELISTOR (methylnaltrexone bromide) -treated patients had a significantly higher rate of laxation within 4 hours of the double-blind dose (62% for 0.15 mg/kg and 58% for 0.3 mg/kg) than did placebo-treated patients (14%); p < 0.0001 for each dose versus placebo (Figure 1).

Study 2 compared double-blind, subcutaneous doses of RELISTOR (methylnaltrexone bromide) given every other day for 2 weeks versus placebo. Patients received opioid medication ≥ 2 weeks prior to receiving study medication. During the first week (days 1, 3, 5, 7) patients received either 0.15 mg/kg RELISTOR (methylnaltrexone bromide) or placebo. In the second week the patient's assigned dose could be increased to 0.30 mg/kg if the patient had 2 or fewer rescue-free laxations up to day 8. At any time, the patient's assigned dose could be reduced based on tolerability. Data from 133 (62 RELISTOR (methylnaltrexone bromide) , 71 placebo) patients were analyzed. There were 2 primary endpoints: proportion of patients with a rescue-free laxation within 4 hours of the first dose of study medication and proportion of patients with a rescue-free laxation within 4 hours after at least 2 of the first 4 doses of study medication. RELISTOR (methylnaltrexone bromide) -treated patients had a higher rate of laxation within 4 hours of the first dose (48%) than placebo-treated patients (16%); p < 0.0001 (Figure 1). RELISTOR (methylnaltrexone bromide) -treated patients also had significantly higher rates of laxation within 4 hours after at least 2 of the first 4 doses (52%) than did placebo-treated patients (9%); p < 0.0001. In both studies, in approximately 30% of patients, laxation was reported within 30 minutes of a dose of RELISTOR (methylnaltrexone bromide) .

Figure 1. Laxation Response Within 4 Hours of the First Dose

In both studies, there was no evidence of differential effects of age or gender on safety or efficacy. No meaningful subgroup analysis could be conducted on race because the study population was predominantly Caucasian (88%). The rates of discontinuation due to adverse events during the double blind placebo controlled clinical trials (Study 1 and Study 2) were comparable between RELISTOR (methylnaltrexone bromide) (1.2%) and placebo (2.4%).

Durability of Response

Durability of response was demonstrated in Study 2, in which the laxation response rate was consistent from dose 1 through dose 7 over the course of the 2-week, double-blind period.

The efficacy and safety of methylnaltrexone bromide was also demonstrated in open-label treatment administered from Day 2 through Week 4 in Study 1, and in two open-label extension studies (Study 1EXT and Study 2EXT) in which RELISTOR (methylnaltrexone bromide) was given as needed for up to 4 months. During open-label treatment, patients maintained their regular laxative regimen. A total of 136, 21, and 82 patients received at least 1 open-label dose in studies 1,1EXT, and 2EXT, respectively. Laxation response rates observed during double-blind treatment with RELISTOR (methylnaltrexone bromide) were maintained over the course of 3 to 4 months of open-label treatment.

Opioid Use and Pain Scores

There was no relationship between baseline opioid dose and laxation response in methylnaltrexone bromide-treated patients in these studies. In addition, median daily opioid dose did not vary meaningfully from baseline in either RELISTOR (methylnaltrexone bromide) -treated patients or in placebo-treated patients. There were no clinically relevant changes in pain scores from baseline in either the methylnaltrexone bromide or placebo-treated patients.

Last reviewed on RxList: 8/13/2010
This monograph has been modified to include the generic and brand name in many instances.